Trimegestone (tmg) for treatment of preterm birth

ABSTRACT

As disclosed herein, novel compositions including steroid hormones, such as trimegestone (TMG) and progesterone (P4), provide treatments for term and preterm labor with significant effects on the delay of delivery. Delay and block of delivery occurs when both P4 and TMG are administered late in gestation in pregnant rat and guinea pig animal models. TMG exhibits remarkable drug efficacy, achieving the same inhibition as P4, but at much lower doses. These hereto unknown effects of TMG on the processes of cervical ripening and uterine contraction provide a novel approach for extending pregnancy term, including reducing a likelihood of preterm and/or term labor, along with improved methods of administration. Other diseases and/or conditions may be treated with TMG, such as dysmenorrhea or luteal insufficiency for sustaining pregnancy.

This application claims priority to U.S. Ser. No. 61/311,944 filed Mar.9, 2010, US Ser. No. 61/407,388 filed Oct. 27, 2010 and to U.S. Ser. No.61/434,309 filed Jan. 19, 2011, the contents of all of which are hereinincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to methods and compositions related toobstetrics and gynecological diseases and/or conditions.

BACKGROUND

All publications herein are incorporated by reference to the same extentas if each individual publication or patent application was specificallyand individually indicated to be incorporated by reference. Thefollowing description includes information that may be useful inunderstanding the present invention. It is not an admission that any ofthe information provided herein is prior art or relevant to thepresently claimed invention, or that any publication specifically orimplicitly referenced is prior art.

Preterm birth (less than 37 completed weeks of gestation) is one of themajor problems and challenges in obstetrics. The frequency of pretermbirths is about 12-13% in the USA and 5-9% in many other developedcountries.^(1,2) Despite all efforts to reduce the number of pretermbirths the problem is continuing to escalate. Since 1990 the percentageof births delivered preterm has risen more than 20 percent and is 36percent higher since the early 1980s in the USA.³ Preterm birth is notonly a major determinant of neonatal and infant morbidity, includingneurodevelopmental handicaps, chronic respiratory problems,intraventricular hemorrhage, infection, retrolental fibroplasia, andnecrotizing enterocolitis, but it is also the single most importantcause of perinatal mortality in North America, Europe and particularlyin undeveloped countries.⁴ Additionally, the neonatal and long-termhealth care costs of preterm infants impose a considerable economicstrain both on individual families and on healthcare costs (>$26.2billion in 2005 in the USA).^(5,53) There is a need in the art for noveland effective treatments for preterm delivery.

Both uterine and cervical functions play important roles in the onsetand progression of term and preterm labor and delivery. Ripening of thecervix is an inflammatory-like reaction with infiltration of leukocytes,increase of cytokines (interleukin (IL)-1 and IL-8) and an increase inmetalloproteinases (MMPs), with MMPs playing a key role in ECMremodeling.^(8,9,10) Following cervical ripening, uterine contractionand cervical dilation results in delivery of the fetus. Uterinecontraction results from the biomechanical coupling of actin and myosin,which depends on the phosphorylation of myosin by myosin light-chainkinase (MLCK). The activation of MLCK by various uterotonins, includingoxytocin and prostaglandins, fosters actin-myosin coupling, leading tosynchronous high-amplitude activity in cell-cell connections thatgenerate contractions in the uterus.

Both processes of cervical ripening and uterine contractility areregulated by steroid hormones (in particular progesterone (P4) andestrogen) and progesterone has been known to be used for recurrent orhigh risk preterm labor (PTL).^(17-26,32) However, P4 used to treatpreterm labor and uterine contractile disorders is often deliveredthrough inconvenient and less effective routes of vaginal, oral orintramuscular delivery. Further, P4 exhibits some measure ofnon-specificity for non-progesterone receptors, leading to potentiallyundesirable side effects.

Trimegestone (TMG), a 19-norpregnane derivative progestin, has been usedin clinical trials as a proposed treatment for hormone replacementtherapy, as well as for oral contraception.⁵⁷⁻⁶² To date, the efficacyof compounds such as TMG has not been shown in treatments for pre-termpregnancy. As a “next generation” progestin (i.e., synthetic orexogenous progestogen), TMG exhibits a 6-fold higher affinity forprogesterone receptor (PR) than P4, with much greaterpotency.^(11,12)This activity is coupled with higher selectivity for thePR compared to other steroid hormone receptors. For example, TMG bindswith low affinity to the androgen, glucocorticoid and mineralocorticoidreceptor and has no measurable affinity for the estrogen receptor.^(12,14,64,65) These pharmacological differences may result in notablydifferent biological effects. For example, TMG also exhibits adifferential effect on MMP expression in cultured stromal cells whencompared to P4 administration.¹³ TMG also exhibits antiestrogenicactivity in processes related to rat uterine decidualization andovulation assays, and possesses the highest level of estrogenic activityantagonism in the uterine endometrium among reference progestins.⁶⁷Together, these results suggest TMG may be a potent compound forinhibiting cervical ripening and uterine contractility, with furtheropportunities to apply TMG in new therapeutic avenues, such asdysmenorrhea.⁶⁸

These features of TMG present intriguing questions of how TMGapplication for preterm pregnancy treatment compares to P4administration, and if higher PR specificity coupled with differentmechanisms of action may lead to improved methods of treatment and/oradministration.¹¹

SUMMARY OF THE INVENTION

The following embodiments and aspects thereof are described andillustrated in conjunction with compositions and methods which are meantto be exemplary and illustrative, not limiting in scope. In oneembodiment, the invention includes a method of extending pregnancy termin a subject in need thereof, including providing a quantity of acomposition comprising a 19-norprogesterone, or a pharmaceuticalequivalent, derivative, analog, and/or salt thereof, and administeringthe quantity of the composition to the subject in need thereof Inanother embodiment, the 19-norprogesterone is a compound of the formula:

or a pharmaceutical equivalent, derivative, analog, and/or salt thereof.In another embodiment, the composition further includes one or moresolubilizing factors. In one embodiment, the one or more solubilizingfactors is selected from the group of: cyclodextrins, sesame oil, fishoil, corn oil, olive oil, coconut oil, krill oil, omega fatty acids,mineral oil, peppermint oil, flaxseed oil, vitamin E oil, argan oil,saline solution and glucose solution. In another embodiment, thecomposition is administered through nasal, oral, subcutaneous,transmucosal, transdermal, parenteral, implantable pump, continuousinfusion, topical, intradermal, intravenous, intramuscular,intraperitoneal, inhalation, rectal, non-vaginal and/or vaginaldelivery. In one embodiment, the method further includes administeringof one or more compounds selected from the group consisting of:nifedipine, indomethacin, magnesium sulfate, oxytocin antagonists, andtocolytics. In another embodiment, the one or more compounds isadministered after administering the quantity of the compositioncomprising a 19-norprogesterone, or a pharmaceutical equivalent,derivative, analog, and/or salt thereof In another embodiment, thecomposition is administered at least twice daily. In another embodiment,the composition is administered to the subject in the range of: 0.01-0.1mg, 0.1-0.5mg 0.5-1mg, 1-5mg, 5-10mg, 10-15mg, 15-20mg, and/or 20-100mg. In one embodiment, the pregnancy term is at least 22 weeks. In oneembodiment, the pregnancy term is at least 37 weeks.

Another embodiment of the present invention provides a pharmaceuticalcomposition, including a therapeutically effective amount of a19-norprogesterone, or a pharmaceutical equivalent, derivative, analog,and/or salt thereof, and a pharmaceutically acceptable carrier. In oneembodiment, the 19-norprogesterone is a compound of the formula:

or a pharmaceutical equivalent, derivative, analog, and/or salt thereof.In another embodiment, the composition further includes one or moresolubilizing factors. In another embodiment, the one or moresolubilizing factors is selected from the group of: cyclodextrins,sesame oil, fish oil, corn oil, olive oil, coconut oil, krill oil, omegafatty acids, mineral oil, peppermint oil, flaxseed oil, vitamin E oil,argan oil, saline solution and glucose solution. In another embodiment,the pharmaceutical composition further includes one or more compoundsselected from the group consisting of: nifedipine, indomethacin,magnesium sulfate, oxytocin antagonists, and tocolytics. In anotherembodiment, the pharmaceutical composition is provided in a dosage inthe range of: 0.01-0.1 mg, 0.1-0.5 mg 0.5-1 mg, 1-5 mg, 5-10 mg, 10-15mg, 15-20 mg, and/or 20-100 mg.

Another embodiment of the present invention provides a method oftreating a disease and/or condition in a subject in need thereofincluding providing a quantity of a composition comprising a19-norprogesterone, or a pharmaceutical equivalent, derivative, analog,and/or salt thereof; and administering the quantity of the compositionto the subject in need thereof.

In another embodiment, the 19-norprogesterone is a compound of theformula:

or a pharmaceutical equivalent, derivative, analog, and/or salt thereof.In another embodiment, the composition further includes one or moresolubilizing factors. In another embodiment, the one or moresolubilizing factors is selected from the group of: cyclodextrins,sesame oil, fish oil, corn oil, olive oil, coconut oil, krill oil, omegafatty acids, mineral oil, peppermint oil, flaxseed oil, vitamin E oil,argan oil, saline solution and glucose solution. In another embodiment,the composition is administered through nasal, oral, subcutaneous,transmucosal, transdermal, parenteral, implantable pump, continuousinfusion, topical, intradermal, intravenous, intramuscular,intraperitoneal, inhalation, rectal, non-vaginal and/or vaginaldelivery. In another embodiment, composition further includesadministering one or more compounds selected from the group of:nifedipine, indomethacin, magnesium sulfate, oxytocin antagonists, andtocolytics. In another embodiment, the one or more compounds isadministered after administering the quantity of the compositioncomprising a 19-norprogesterone, or a pharmaceutical equivalent,derivative, analog, and/or salt thereof. In another embodiment, thecomposition is administered twice daily. In another embodiment,composition is administered to the subject in the range of: 0.01-0.1 mg,0.1-0.5 mg 0.5-1 mg, 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, and/or 20-100mg. In another embodiment, disease and/or condition is selected from thegroup of: preterm labor, term labor, luteal insufficiency, dysmenorrhea,dysfunctional uterine bleeding, and combinations thereof. In anotherembodiment, the disease and/or condition is dysmenorrhea. In anotherembodiment, the disease and/or condition is luteal insufficiency.

BRIEF DESCRIPTION OF THE FIGURES

Exemplary embodiments are illustrated in referenced figures. It isintended that the embodiments and figures disclosed herein are to beconsidered illustrative rather than restrictive.

FIG. 1 depicts, in accordance with an embodiment herein, a graphcomparing the effects of progesterone (P4) and trimegestone (TMG),administered subcutaneously (s.c.), on delay of delivery in pregnantrats. Note that in this and subsequent figures 100% delay indicates 80hours beyond the normal delivery time on day 22 of gestation.

FIG. 2 depicts, in accordance with an embodiment herein, a graphcomparing the effects of progesterone (P4) and trimegestone (TMG),administered topically, on delay of delivery on pregnant rats.

FIG. 3 depicts, in accordance with an embodiment herein, a graphcomparing the effect on delay of delivery by different dosages oftrimegestone (TMG), administered either topically or subcutaneously(s.c.)as indicated.

FIG. 4 depicts, in accordance with an embodiment herein, a graphcomparing the effect on delay of delivery by different dosages ofprogesterone (P4), administered either topically or subcutaneously(s.c.) as indicated.

FIG. 5: depicts, in accordance with an embodiment herein, comparison ofdose/response effects of subcutaneous (s.c.) treatments betweentrimegestone (TMG) and progesterone (P4) on delay of delivery inpregnant rats. Much lower doses of TMG are required for complete block(>80 hours beyond normal delivery on day 22) compared to P4 block ofdelivery. Percent inhibition of delivery is shown where 80 hour delay(day 25) denotes 100 percent inhibition. Complete inhibition can be seenwith s.c TMG at much lower doses than s.c P4 (0.5 mg vs. 2 mg).

FIG. 6 depicts, in accordance with an embodiment herein, comparison ofdose/response effects of topical progesterone (P4) or trimegestone (TMG)in delay of delivery in pregnant rats. Much lower doses of TMG arerequired for complete block (>80 hours beyond normal delivery on day 22)compared to P4 block of delivery. Percent inhibition of delivery isshown at 80 hour delay (day 25) denoted as 100 percent inhibition.Complete inhibition can be seen with topical TMG at much lower dosesthan topical P4 (0.1 mg vs. 15 mg).

FIG. 7 depicts, in accordance with an embodiment herein, dose/responseeffects topical and subcutaneous (s.c) progesterone (P4) on delay ofdelivery in rats. Dose response curves shows that lower daily doses arerequired for complete block of delivery when P4 is administered s.c.when given on day 20 of gestation. Complete block of delivery is seen at80 hour delay (day 25) and denoted by 100 percent inhibition. Topicalgroup received treatments twice a day while subcutaneous group receiveda single daily treatment. Subcutaneous administration of P4 requiredlower doses than topical to completely block delivery (2 mg vs. 15 mg).

FIG. 8 depicts, in accordance with an embodiment herein, effects oftrimegestone (TMG) between topical or subcutaneously (s.c) on delay ofdelivery in rats. Note that a lower dose is required for complete blockof delivery when TMG is administered topically. Complete block ofdelivery is seen at 80 hour delay (day 25) and denoted by 100 percentinhibition. Topical group received treatments twice a day whilesubcutaneous group received a single daily treatment. Each pointrepresents total amount of TMG given per day. Topical administration ofTMG required slightly lower doses than subcutaneous to completely blockdelivery, possible because TMG was given twice daily due to a shorterhalf-life.

FIG. 9 depicts, in accordance with an embodiment herein, sex of pups ofrats treated with either of trimegestone (TMG) or vehicle beginning onday 13 of gestation until day 22. TMG treated and controls demonstratednon-significant differences between the number of females to males. ForTMG Group (N=9), TMG was administered from day 13 to day 21, when motherrats were sacrificed and pups were taken from uterus and placed withsurrogate mother rat that had just delivered. For vehicle control (N=9),BB:CO (1:4) mixture was administered subcutaneously in 0.2 ml volumefrom day 13 to day 21 of gestation. As shown, no change is sex ratio isobserved.

FIG. 10 depicts, in accordance with an embodiment herein, photograph ofmale (right) and female (left) fetuses on day 22 of gestation aftertreatment with TMG beginning on day 13 of pregnancy. Note that thedistance between the external genitalia and the anus is greater distancein males.

FIG. 11 depicts, in accordance with an embodiment herein, effects ofprostaglandin E2 (PGE2), or trimegestone (TMG) and its combination ondelay of delivery in Guinea Pig. Preterm delivery rates of guinea pigstreated with vehicle, TMG and PGE2 and TMG plus PGE2. Vehicle only groupwas treated with 0.5ml s.c of a mixture of benzyl benzoate and castoroil (1:4) on days 44-47 and 0/4 guinea pigs delivered. TMG only groupwas treated with 4 mg/day s.c on days 44-47 and 1/4 guinea pigsdelivered. PGE2 only group was treated with 3 mg/day in saline vehicleon days 46, 47 and 4/6 guinea pigs delivered. PGE2 plus TMG group wastreated with TMG from days 44-47 and PGE2 on days 46-47 and 2/6 guineapigs delivered.

DESCRIPTION OF THE INVENTION

All references cited herein are incorporated by reference in theirentirety as though fully set forth. Unless defined otherwise, technicaland scientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. Singleton et al., Dictionary of Microbiology and MolecularBiology 3rd ed., J. Wiley & Sons (New York, N.Y. 2001); March, AdvancedOrganic Chemistry Reactions,

Mechanisms and Structure 5th ed., J. Wiley & Sons (New York, N.Y. 2001);and Sambrook and Russel, Molecular Cloning: A Laboratory Manual 3rd ed.,Cold Spring Harbor Laboratory Press (Cold Spring Harbor, N.Y. 2001), andRemington: The Science and Practice of Pharmacy (Gennaro ed. 20thedition, Williams & Wilkins Pa., USA) (2000) provide one skilled in theart with a general guide to many of the terms used in the presentapplication.

One skilled in the art will recognize many methods and materials similaror equivalent to those described herein, which could be used in thepractice of the present invention. Indeed, the present invention is inno way limited to the methods and materials described.

“Treatment” and “treating,” as used herein refer to both therapeutictreatment and prophylactic or preventative measures, wherein the objectis to prevent or slow down (lessen) the targeted pathologic condition,prevent the pathologic condition, pursue or obtain beneficial results,or lower the chances of the individual developing the condition even ifthe treatment is ultimately unsuccessful. Those in need of treatmentinclude those already with the condition as well as those prone to havethe condition or those in whom the condition is to be prevented.

As used herein, the abbreviation “TMG” means trimegestone (also known asRU-27987), or a compound of the formula:

As used herein, the abbreviation “P4” means progesterone, or a compoundof the formula:

As used herein, promegestone (also known as R5020) has the formula:

As used herein, nomcgcstrol has the formula:

As used herein, nomegestrol acetate has the formula:

As used herein, demegestone has the formula:

As used herein, nestorone has the formula:

Labor is a multifactorial process involving several different pathwaysconverging together to result in the birth of an animal. During most ofthe pregnancy term, the cervix forms a firm, rigid closed stateprotecting the fetus from the environment, while the uterus remainsrelatively quiescent. An activation phase involving uterine stretch isfollowed by a stimulation phase with a progressive cascade of eventsinvolving cervical ripening, uterine contractility, decidual and fetalmembrane activation.

A key step in this cascade of events, cervical ripening, is an activebiochemical process occurring independently of the processes underlyinguterine contractility. The cervix is dominated by fibrous connectivetissue that is composed of an extracellular matrix which consists mostlyof collagen (70% type I and ˜30% type 111⁶) with elastin andproteoglycans and a cellular portion that consists of smooth muscles,fibroblasts, epithelium and blood vessels. Studies have shown that theprocess of cervical ripening is associated with a strong reorganizationof the extracellular matrix (ECM), especially collagen. Not only doesthe concentration decrease by 30-70%, but there is also a switch frominsoluble to more soluble collagen.^(6,7) Ripening of the cervix is aninflammatory-like reaction with infiltration of leukocytes, increase ofcytokines (interleukin (IL)-1 and IL-8) and an increase inmetalloproteinases (MMPs), with MMPs playing a key role in ECMremodeling.^(8,9,10)

Cervical ripening, followed by uterine contraction and dilation of thecervix, ultimately results in the delivery of the fetus. Uterinecontraction results from the coupling of actin and myosin, which dependson the phosphorylation of myosin by myosin light-chain kinase (MLCK).MLCK is activated by various uterotonins, including oxytocin andprostaglandins. Actin-myosin couplings, operating through cell-to-cellconnections, generate the biomechanical signal leading to synchronoushigh-amplitude uterine contractions during labor.

These distinct processes of cervical ripening and uterine contractilityare at least partially regulated by steroid hormones (in particular,progesterone (P4) and estrogen). For example, progesterone has been asan effective treatment for recurrent or high risk preterm labor(PTL).^(17-26,12) However, steroid hormones play divergent roles inthese different processes. For example, during cervical ripening,important enzymes such as MMPs govern

ECM remodeling, via the degradation and turnover of key proteins such ascollagen.^(8,9,10) As P4 is considered to be the principal suppressor ofMMP expression in the endometrium, inhibiting MMP expression andactivity may serve as the mechanism for slowing the process of cervicalripening, and suppressing preterm delivery. For uterine contractility,synchronous high-amplitude contractions in cell-cell connections arefacilitated by the formation of gap junctions. The formation of thesegap junctions is highly dependent on estrogen; estrogen activation, inturn, is induced by a functional progesterone withdrawal at term. Thus,compounds such as P4 operate through distinct and divergent mechanismsof action in the context of cervical ripening and uterine contractility.

Despite the effective use of compounds such as P4 for treating pretermlabor and uterine contractile disorders, there are several significantlimitations and drawbacks. Current administration techniques oftendeliver P4 as crystalline progesterone in micronized form, thererequiring the inconvenient and less effective routes of vaginal, oral orintramuscular delivery. Further, P4 exhibits some measure ofnon-specificity for non-progesterone receptors, leading to potentiallyundesirable side effects.

Trimegestone (TMG) is a member of the 19-norprogesterone derivativefamily, wherein the core 19-norprogesterone structure originates fromthe pregnane (19-norpregnane) structure, but possesses one less carbonatom due to a radical methyl removed at C-19. Removal of carbon 19 fromsteroid hormones, such as testosterone, changes the major hormonaleffect from androgenic to prostogenic, with some “19-nor” steroidsacting as prodrugs, and other being active in unchanged form. Exemplarymembers of the 19-norprogesterone family include trimegestone,promegestone, nomegestrol, nomegestrol acetate, demegestone, andnestorone. A key feature of the 19-norprogesterone family of moleculesis high selectivity for the

PR. For example, the relative binding affinity (RBA) for TMG-PRinteractions is 588, but for TMG-mineralocorticoid receptors (MR), RBAis only 42, thereby demonstrating a high level of separation between RBAfor PR compared to other classical steroid hormone receptors.^(12,14)This high specificity for PR results in both greater potency(approximately 6 times higher than P4), but also reduces undesirableside-effects via interactions with other steroid hormone receptors.

The potentially effective use of 19-norprogesterone molecules, such asTMG, for suppressing term and pre-term delivery is suggested by severalreports demonstrating important interactions with key molecules involvedin both cervical ripening and uterine contractility processes. Forexample, in cultured stromal cells, TMG has been reported to exhibittighter control of MMP expression, such as MMP-1 and MMP-3, compared toP4 further including suppression of MMP-9+ cell proliferation.¹³Further, the activity of TMG on the rat uterine decidualization andovulation assays is similar to other progestins, but TMG was the mostpotent antagonist of estrogenic activity in the uterine endometrium whencompared to any of several reference progestins tested.⁶⁸

This potent effect of TMG in the uterus endometrium further suggests newtherapeutic avenues, such as treatment of dysmenorrhea. Decidulation hasbeen reported to control eutopic endometrial stromal cell-mediatedcontractility⁶⁹ and application of TMG represents a novel and integralmechanism of regulating the physiological endometrial tissue remodelingprocess that occurs during menstrual cycles. Similarly, TMG may also beused in early pregnancy to enhance implantation, as a means tosupplement endogenous progesterone levels that are low (lutealinsufficiency) for the purpose of sustaining pregnancy.

Another key feature of 19-norprogesterone family members, such as TMG,is potential use in more convenient and effective delivery routes. Asdescribed, compounds such as P4 have demonstrated effective results whenused for treating preterm labor and uterine contractile disorders.However, delivery is often achieved by inconvenient and less effectiveroutes of vaginal, oral or IM administration. By contrast, TMG has shownpromise for use in topical applications, such as transdermalcontraceptive applications.¹⁵

Despite these positive results, TMG has yet to be utilized in theprevention and treatment of preterm and term labor and no studies havebeen published suggesting the potential of TMG as a potential treatmentfor the prevention and treatment of term and preterm labor. Withoutbeing bound by any particular theory, it is suggested that TMG can delaydelivery in rats when administered either subcutaneously or topicallylate in gestation and at lower doses than progesterone (P4), that TMGprevents prostaglandin-induced preterm delivery in guinea pigs and thatexogenous TMG and P4 are suitable candidates for treatment of pretermand term labor.

To establish the potential use of TMG as an effective treatment forsuppressing pre-term delivery birth, the inventors conducted two studiesusing animal models. In one study, TMG and P4 were both given topicallyand parenterally on term delivery in pregnant rats and to assess theability of TMG to suppress preterm delivery, in pregnant guinea pigs, amodel thought to be similar to human endocrine control of pregnancy andparturition.

In the first study, pregnant rats were treated daily beginning on day 20of gestation with topical P4 (fish oil vehicle) or topical TMG (fish oilvehicle), along with subcutaneous P4 administration (sesame oil vehicle)or subcutaneous TMG administration (benzyl benzoate (BB) and castor oil(CO) vehicle), and vehicle as controls. Various dosage of topical andsubcutaneous P4 or TMG administration were applied in order to assessdrug efficacy. Delivery times were observed in the animals, wherein timeof delivery was measured as the number of hours elapsed after 8 am onday 22 of gestation, and 80 hours being defined as complete block ofdelivery and time of sacrifice. The inventors discovered that TMGcompletely blocks term delivery in rats (80 hrs. inhibition) at muchlower doses (ca. 30×, 0.5 mg TMG vs. 15 mg P4, P<0.05, topically, andca. 4×, 0.5 mg TMG vs. 2 mg P4, P<0.05, subcutaneous) when compared toP4.

In the second study, pregnant guinea pigs were treated with PGE2 (salinevehicle) on days 46 and 47 of gestation to induce pretermdelivery^(66,67) and sacrificed on day 48. Some animals were given TMG(BB and CO vehicles) beginning on day 44 of gestation until day 47 whilealso being treated with PGE2 on days 46 and 47, where PGE2 effectivelyinduces preterm delivery. All guinea pigs were sacrificed on day 48. Theinventors found that PGE2 induced preterm delivery is inhibited bysimultaneous treatment with TMG. None of the guinea pigs treated withTMG and PGE2 delivered, while ⅔ PGE2-only treated animals delivered (all3 exhibited vaginal bleeding).

Overall, the inventors found that TMG effectively inhibits both termdelivery in rats and PGE2-induced preterm delivery in guinea pigs. Bothtopical and parenteral administration of P4 and TMG are equallyefficacious, but TMG is more potent than P4 in delaying delivery inrats. Together, these results demonstrate that TMG is an effective andpotent molecule for suppressing preterm and term labor and delivery.

As described herein, the present invention provides a method ofextending pregnancy term, including reducing a likelihood of pretermand/or term labor, in a subject by administering a therapeuticallyeffective amount of a composition comprising a progestogen, or apharmaceutical equivalent, derivative, analog, and/or salt thereof Inanother embodiment, the progestogen is 19-norprogesterone or apharmaceutical equivalent, derivative, analog, and/or salt thereof. Inanother embodiment, the 19-norprogesterone pharmaceutical equivalent,derivative, analog, and/or salt thereof is trimegestone. In anotherembodiment, the composition comprises a compound of the formula:

or a pharmaceutical equivalent, derivative, analog, and/or salt thereof,and a pharmaceutically acceptable carrier.

In another embodiment, the 19-norprogesterone pharmaceutical equivalent,derivative, analog, and/or salt thereof is promegestone, nomegestrol,nomegestrol acetate, demegestone, nestorone. In another embodiment, thesubject is a human. In another embodiment, the subject is a rat. Inanother embodiment, the subject is a guinea pig. In another embodiment,the composition is administered to the subject topically. In anotherembodiment, the composition is administered to the subject parenterally.In another embodiment, the effective dosage ranges between 0.05 mg and100 mg. In another embodiment, the effective dosage ranges between 0.05mg and 30 mg. In another embodiment, the dosage is 0.05 and 0.50 mg.

In other embodiments, the pregnancy term is at least 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 or 42weeks. In other embodiments, the pregnancy term is extended by 1, 2, 3,4, 5, 6, or 7 or more days. In other embodiments, the pregnancy term isextended by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21 or 22 weeks. In some embodiments, preterm labor occursduring weeks 22-37 of pregnancy term. In other embodiments, term laboroccurs during weeks 37-42 of pregnancy term. In some embodiments,preterm birth occurs during weeks 22-37 of pregnancy term. In otherembodiments, term birth occurs during weeks 37-42 of pregnancy term.

As described herein, the present invention also provides apharmaceutical composition comprising a therapeutically effective amountof a compound of the formula:

or a pharmaceutical equivalent, derivative, analog, and/or salt thereof,and a pharmaceutically acceptable carrier.

In some embodiments, the generic class of “19-nor” steroids, whichfurther includes members of the 19-norprogesterone family, may act asprodrugs, and other being active in unchanged form. Exemplary members ofthe 19-norprogesterone family include trimegestone, promegestone,nomegestrol, nomegestrol acetate, demegestone, and nestorone.

Examples of 19-norprogesterone derivatives and analogs include thosedescribed in U.S. Pat. Nos. 3,328,432, 5,223,492, 5,290,771, 6,790,971,4,263,290, and 4,874,754. Further examples include, 17α-hydroxy 6,21-dimethyl 3,20-dioxo 19-nor pregna 4,6-diene, 17α-acetoxy6,21-dimethyl 3,20-dioxo 19-nor pregna 4,6-diene, 17αbutyryloxy6,21-dimethyl 3,20-dioxo 19-nor pregna 4,6-diene,17αtetrahydropyranyloxy 6,21-dimethyl 3,20-dioxo 19-nor pregna4,6-diene, 17αcaproyloxy 6,21-dimethyl 3,20-dioxo 19-nor pregna4,6-diene, 17α-heptanoyloxy 6,21-dimethyl 3,20-dioxo 19-nor pregna4,6-diene, and 3,20-dioxo 17α, 21-dimethyl 19-nor pregna 4,9-diene.

Other examples of 19-norprogesterone derivatives and analogs include11β-N-(2-dimethylaminoethyl)-17β-hydroxy-N-methyl-3-oxo-Δ-estradien-undecanamide,N-butyl-4-(3,17β-dihydroxy-Δestratrien-11β-yl)-N-methyl-benzeneoctanamide,3,17β-dihydroxy-N-methyl-N-isopropyl-11β-Δ-estratrien-undecanamide,N-butyl-3,17β-dihydroxy-N-methyl-19-nor-11β-(17α-Δ-pregnatrien-20-yn)-undecanamide,3,17β-dihydroxy-N-methyl-N-isopropyl-19-nor-11β-17α-Δ-pregnatrien-20-yn)-undecanamide,[[8-(3,17β-dihydroxy-Δ.sup-estratrien-11β-yl)-octyl]-oxy]-N-methyl-N-isopropyl-acetamide,N-butyl-8-[4-(3,17β-dihydroxy-Δ-estratrien-11β-yl)-phenoxy-N-methyloctanamide,N-butyl-[5-[4-(3,17β-dihydroxy-Δ-estratrien-11β-yl)-phenoxy]-pentoxy]-N-methyl acetamide,2-[(7-[4-(3,17β-dihydroxy-Δ-estratrien-11β-yl)-phenyl]-6-heptlyl]oxy]-N-butyl-N-methylacetamide, 3,17β-dihydroxy-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl1-estratrien-11β-yl undecanamide,8-[4-(3,17β-dihydroxy-Δ-estratrien-11β-yl)-phenyl]-N-butyl-N-methyloctynamide, β-N-(2-dimethylaminoethyl)-17β-hydroxy-N-methyl-3-oxo-Δ-estradien-undecanamide, N-butyl-4-(3,17β-dihydroxy-Δ-estratrien- 11 β-yl)-N-methyl-benzene octanamide,3,17β-dihydroxy-N-methyl-N -isopropyl-11 β-Δ-estratrien-undecanamide,N-butyl-3,17 β-dihydroxy-N-methyl-19-nor-11β-(17α-Δ-pregnatrien-20-yn)-undecanamide, 3,17β-dihydroxy-N-methyl-N-isopropyl-19-nor-11β-17α-Δ-pregnatrien-20-yn)-undecanamide,[[8 -(3,17 β-dihydroxy-Δ-estratrien-11β-yl)-octyl]-oxy]-N-methyl-N-isopropyl-acetamide, N-butyl-8-{4-(3,17β-dihydroxy Δ-estratrien-11β-yl)-phenoxy-N-methyl octanamide,N-butyl-[5-[4-(3,17β-dihydroxy-Δ-estratrien-11β-yl)-phenoxy]-pentoxy]-N-methylacetamide, 2-[(7-[4-(3,17β-dihydroxy-66-estratrien-11β-yl)-pheny]-6-heptyl]-oxy]-N-butyl-N-methyl acetamide,3,17β-dihydroxy-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-Δ-estratrien-11β-yl]-undecanamideand N-[4-(3,17 β-dihydroxy-Δ-estratrien-11β-yl)-phenyl-N-butyl-N-methyloctynamide.

Other examples of 19-norprogesterone derivatives and analogs include11β-N-(2-dimethylaminoethyl)-17β-hydroxy-N-methyl-3-oxo-Δ-estradien-undecanamide,11β-(4-((7-(butylmethylamino)-carbonyl)-heptyl)-oxy-phenyl)-Δ-estratrien-3-ol-17β-yl,butanedioate of11β-(4-((7-((butylmethylamino)-carbonyl)-heptyl)-oxy)-phenyl)-Δ-estratrien-3-ol- 17β-yl and its sodium salt,N-butyl-2-(6-(4-(67-estratrien-3,17β-diol-11β-yl)-phenoxy)-hexyloxy-N-methyl-acetamide,N-butyl-8-(4-(Δ-estratrien-3,17β-diol-11β-yl)-phenoxy)-N-methyl-2-octynamide,N-butyl-2-((5-(4-(Δ-estratrien-3,17β-diol-11β-yl)-phenyl)-pentyl)-thio)-N-methylacetamide,N-butyl-4-(Δ-estratrien-3,17β-diol-11β-yl)-N-methyl-benzenenonamide,N-butyl-2-((5-(4-Δ-estratrien-3,17β-diol-11β-yl)-phenyl)-pentyl)-oxy)-N-methyl-acetamide,and 2-((8-(Δ-19-nor-17α-pregnatrien-3,17β-diol-20-yn-11β-yl)-octyl)-oxy)-N-methyl N-(1 -methylethyl)-acetamide.

Other examples of 19-norprogesterone derivatives and analogs include7α-{4 -[2-(dimethylamino)-ethoxy]-phenyl}-Δ-estratriene-3,17-diol,7α-{4-[2-dimethylamino)-ethoxy]-phenyl}- 17β-hydroxy- Δ-estren-3 -one,7β-{4-[2-(dimethylamino)-ethoxy]-phenyl}-Δ-estratriene-3,17β-diol,7β-{4-[2-(dimethylamino)-ethoxy]-phenyl}-17β-hydroxy- Δ-estren-3-one;7α-[4-(dimethylamino)-phenyl]-estratriene-3,17β-diol,7α-(4-methoxyphenyl)-Δ-estratriene-3,17β-diol-7α-[4-(methylthio)-phenyl]-estren-17β-ol-3 -one and 7α-[4-methylthio)-phenyl]- Δ-estratriene-3,17β-diol.

As described herein, the present invention provides a method forinhibiting preterm and/or term birth or preventing preterm birth in asubject in need thereof. In one embodiment, the method includes acomposition comprising a steroid hormone and administering atherapeutically effective amount of the composition to the subject to soas to inhibit preterm and/or term birth or prevent preterm and/or termbirth. In one embodiment, the steroid hormone is a progestogen, or apharmaceutical equivalent, analog, derivative or a salt thereof Inanother embodiment, the progestogen is 19-norprogesterone, or apharmaceutical equivalent, analog, derivative or a salt thereof. Inanother embodiment, the 19-norprogesterone pharmaceutical equivalent,derivative, analog, and/or salt thereof is trimegestone, or apharmaceutical equivalent, analog, derivative or a salt thereof. Inanother embodiment, the 19-norprogesterone pharmaceutical equivalent,derivative, analog, and/or salt thereof is promegestone, nomegestrol,nomegestrol acetate, demegestone, nestorone, or a pharmaceuticalequivalent, analog, derivative or a salt thereof.

As described herein, the present invention also provides a method fordelaying cervical ripening or inhibiting cervical ripening in subjectsin need thereof. In one embodiment, the method includes providing acomposition including a steroid hormone and administering atherapeutically effective amount of the composition to the subject so asto delay cervical ripening or inhibit cervical ripening. In oneembodiment, the steroid hormone is a progestogen, or a pharmaceuticalequivalent, analog, derivative or a salt thereof. In another embodiment,the progestogen is 19-norprogesterone, or a pharmaceutical equivalent,analog, derivative or a salt thereof. In another embodiment, the19-norprogesterone pharmaceutical equivalent, derivative, analog, and/orsalt thereof is trimegestone, or a pharmaceutical equivalent, analog,derivative or a salt thereof. In another embodiment, the19-norprogesterone pharmaceutical equivalent, derivative, analog, and/orsalt thereof is promegestone, nomegestrol, nomegestrol acetate,demegestone, nestorone, or a pharmaceutical equivalent, analog,derivative or a salt thereof In some embodiments, cervical ripening maybe assessed by directly or indirectly measuring the dissolution ofconnective tissue, according to any number of methods known in the art.

As described herein, the present invention also provides a method forinhibiting myometrial contractility in a subject in need thereof In oneembodiment, the method includes providing a composition including asteroid hormone and administering a therapeutically effective amount ofthe composition to the subject so as to inhibit myometrialcontractility. In one embodiment, the steroid hormone is a progestogen,or a pharmaceutical equivalent, analog, derivative or a salt thereof. Inanother embodiment, the progestogen is 19-norprogesterone, or apharmaceutical equivalent, analog, derivative or a salt thereof. Inanother embodiment, the 19-norprogesterone pharmaceutical equivalent,derivative, analog, and/or salt thereof is trimegestone, or apharmaceutical equivalent, analog, derivative or a salt thereof Inanother embodiment, the 19-norprogesterone pharmaceutical equivalent,derivative, analog, and/or salt thereof is promegestone, nomegestrol,nomegestrol acetate, demegestone, nestorone, or a pharmaceuticalequivalent, analog, derivative or a salt thereof

As described herein, the present invention also provides a method fortreating uterine contractility disorders or inhibiting uterinecontractility disorders in a subject in need thereof In one embodiment,the method includes providing a composition including a steroid hormoneand administering a therapeutically effective amount of the compositionto the subject so as to treat uterine contractility disorders or inhibituterine contractility disorders. In one embodiment, the steroid hormoneis a progestogen, or a pharmaceutical equivalent, analog, derivative ora salt thereof In another embodiment, the progestogen is19-norprogesterone, or a pharmaceutical equivalent, analog, derivativeor a salt thereof In another embodiment, the 19-norprogesteronepharmaceutical equivalent, derivative, analog, and/or salt thereof istrimegestone, or a pharmaceutical equivalent, analog, derivative or asalt thereof. In another embodiment, the 19-norprogesterone ispromegestone, nomegestrol, nomegestrol acetate, demegestone, nestorone,or a pharmaceutical equivalent, analog, derivative or a salt thereof Insome embodiments, a uterine contractility disorder may be diagnoseddirectly or indirectly measuring the muscular contractions associatedwith the sub-endometrial layer of the myometrium, according to anynumber of methods known in the art (e.g., endometrial or contractilewaves). In another embodiment, the uterine contractility disorder isdysmenorrhea, or other menstrual problems, such as premenstrual symptoms(PMS), discomfort from increased uterine contractions,hypercontractility of the uterus, increased blood flow to uterus, anddysfunctional and/or abnormal uterine bleeding.

In one embodiment, the present invention provides a method ofsuppressing preterm and/or term delivery in a subject. In oneembodiment, the method includes providing a composition including asteroid hormone and administering a therapeutically effective amount ofthe composition to the subject so as suppress preterm and/or termdelivery in the subject. In one embodiment, the steroid hormone is aprogestogen, or a pharmaceutical equivalent, analog, derivative or asalt thereof In another embodiment, the progestogen is19-norprogesterone, or a pharmaceutical equivalent, analog, derivativeor a salt thereof In another embodiment, the 19-norprogesteronepharmaceutical equivalent, derivative, analog, and/or salt thereof istrimegestone, or a pharmaceutical equivalent, analog, derivative or asalt thereof. In another embodiment, the 19-norprogesteronepharmaceutical equivalent, derivative, analog, and/or salt thereof ispromegestone, nomegestrol, nomegestrol acetate, demegestone, nestorone,or a pharmaceutical equivalent, analog, derivative or a salt thereof. Insome embodiments, preterm delivery is associated with an increase inprostaglandin levels, such as prostaglandin E2.

In other embodiments, the present invention provides a method oftreating a disease and/or condition in a subject. In some embodiments,the disease and/or condition is characterized by lower endogenousprogesterone levels when compared to healthy subjects. In oneembodiment, disease and/or condition is amenorrhea, luteal insufficiencyin early pregnancy, infertility, hypercontractility of the uterus,cancer prevention when estogen(s) are used, symptoms associated withhormone replacement therapy (such as hot flashes and osteoporosis),preeclampsia (i.e., pregnancy induced hypertension), and dysfunctionaland/or abnormal uterine bleeding.

Since steroid hormones have low solubilities, these hormones may besuspended in or mixed with agents that render the steroid hormonessoluble. For instance, suspending or mixing steroid hormones with agentssuch as cyclodextrins, sesame oil, fish oil, corn oil, olive oil,coconut oil, krill oil, omega fatty acids, mineral oil, peppermint oil,flaxseed oil, vitamin E oil, argan oil, saline solution and/or glucosesolution, facilitates dissolution. In an embodiment, 19-norprogesteroneor pharmaceutical equivalent, derivative, analog, and/or salt thereof,such as trimegestone, may be suspended in or mixed with REPLENS vaginalmoisturizer (available from Lil' Drug Store Products, Inc.).

In another embodiment, the steroid hormones may be mixed with carriermolecules such as cyclodextrins to render the steroid hormone soluble.Examples of cyclodextrins include but are not limited to α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin andmethyl-β-cyclodextrin. For example by encapsulating 19-norprogesteroneor pharmaceutical equivalent, derivative, analog, and/or salt thereof,such as trimegestone, in cyclodextrins and solubilizing it in any of theagents described above, renders the 19-norprogesterone or pharmaceuticalequivalent, derivative, analog, and/or salt thereof soluble and can beused intravenously, topically, parenterally, nasally, subcutaneously,intravascularly, vaginally and/or topically or by other routes ofadministration.

In some embodiments, steroid hormones such as trimegestone,promegestone, nomegestrol, nomegestrol acetate, demegestone, nestoroneand progesterone (P4) or a pharmaceutical equivalent, analog, derivativeor a salt thereof, is suspended in or mixed with omega fatty acid,omega-3-fatty acids, fish oil or peppermint oil and may be usedtopically, parenterally, nasally or by other routes of administration.In one embodiment, administration of 19-norprogesterone orpharmaceutical equivalent, derivative, analog, and/or salt thereof mixedwith fish oil or peppermint oil is topical. For example, topicalapplication of 19-norprogesterone or pharmaceutical equivalent,derivative, analog, and/or salt thereof, such as trimegestone, mixed infish oil can inhibit delivery (such as preterm delivery) in a subject inneed thereof.

In another embodiment, trimegestone, promegestone, nomegestrol,nomegestrol acetate, demegestone, nestorone and progesterone (P4) issuspended in or mixed with saline solution (for example isotonic salinesolution) to solubilize it and is subsequently administered via numerousroutes of administration including but not limited to intravenous,topical, parenteral, nasal, subcutaneous injections, intravascular,vaginal and/or topical or by other routes of administration.

As described herein, the present invention also provides compositionsincluding a steroid hormone and optionally, further includes nifedipine,indomethacin, magnesium sulfate, oxytocin antagonists (for exampleatosiban), and/or other tocolytics. In one embodiment, steroid hormoneand nifedipine may be administered concurrently. In another embodiment,the steroid hormone and nifedipine may be administered sequentially.Similarly, in one embodiment, the steroid hormone and indomethacin maybe administered concurrently. In another embodiment, the steroid hormoneand indomethacin may be administered sequentially. Similarly, in oneembodiment, the steroid hormone and magnesium sulfate may beadministered concurrently. In another embodiment, the steroid hormoneand magnesium sulfate may be administered sequentially. Additionally,the steroid hormone and oxytocin antagonists (for example atosiban) maybe administered concurrently. In another embodiment, the steroid hormoneand oxytocin antagonists (for example atosiban) may be administeredsequentially. In an additional embodiment, the steroid hormone,nifedipine, indomethacin, magnesium sulfate and/or oxytocin antagonistsmay be administered concurrently. Alternatively, the steroid hormone,nifedipine, indomethacin, magnesium sulfate and/or oxytocin antagonistsmay be administered sequentially. In other embodiments, the steroidhormone is administered concurrently or sequentially with tocolytics.

In one embodiment, the steroid hormone is suspended in or mixed withagents that render 19-norprogesterone or pharmaceutical equivalents,derivatives, analogs, and/or salts thereof soluble and is administeredconcurrently or sequentially with nifedipine, indomethacin, magnesiumsulfate, oxytocin antagonists such as atosiban, and/or other tocolytics.In some embodiments, the steroid hormone is a prosteogen. In anotherembodiment, the progestogen is 19-norprogesterone, or a pharmaceuticalequivalent, analog, derivative or a salt thereof. In another embodiment,the 19-norprogesterone pharmaceutical equivalent, derivative, analog,and/or salt thereof is trimegestone, or a pharmaceutical equivalent,analog, derivative or a salt thereof. In another embodiment, the19-norprogesterone pharmaceutical equivalent, derivative, analog, and/orsalt thereof is promegestone, nomegestrol, nomegestrol acetate,demegestone, nestorone, or a pharmaceutical equivalent, analog,derivative or a salt thereof.

As described herein, the present invention also provides pharmaceuticalcompositions including a steroid hormone and optionally, furtherincludes nifedipine, indomethacin, magnesium sulfate, oxytocinantagonists, and/or other tocolytics. In various embodiments, thepharmaceutical compositions according to the invention may be formulatedfor delivery via any route of administration. “Route of administration”may refer to any administration pathway known in the art, including butnot limited to aerosol, nasal, oral, transmucosal, transdermal orparenteral.

The pharmaceutical compositions according to the invention can alsocontain any pharmaceutically acceptable carrier. “Pharmaceuticallyacceptable carrier” as used herein refers to a pharmaceuticallyacceptable material, composition, or vehicle that is involved incarrying or transporting a compound of interest from one tissue, organ,or portion of the body to another tissue, organ, or portion of the body.For example, the carrier may be a liquid or solid filler, diluent,excipient, solvent, or encapsulating material, or a combination thereof.Each component of the carrier must be “pharmaceutically acceptable” inthat it must be compatible with the other ingredients of theformulation. It must also be suitable for use in contact with anytissues or organs with which it may come in contact, meaning that itmust not carry a risk of toxicity, irritation, allergic response,immunogenicity, or any other complication that excessively outweighs itstherapeutic benefits.

The pharmaceutical compositions according to the invention can also beencapsulated, tableted or prepared in an emulsion or syrup for oraladministration. Pharmaceutically acceptable solid or liquid carriers maybe added to enhance or stabilize the composition, or to facilitatepreparation of the composition. Liquid carriers include syrup, peanutoil, olive oil, glycerin, saline, alcohols and water. Solid carriersinclude starch, lactose, calcium sulfate, dihydrate, terra alba,magnesium stearate or stearic acid, talc, pectin, acacia, agar orgelatin. The carrier may also include a sustained release material suchas glyceryl monostearate or glyceryl distearate, alone or with a wax.

The pharmaceutical preparations are made following the conventionaltechniques of pharmacy involving milling, mixing, granulation, andcompressing, when necessary, for tablet forms; or milling, mixing andfilling for hard gelatin capsule forms. When a liquid carrier is used,the preparation will be in the form of syrup, elixir, emulsion or anaqueous or non-aqueous suspension. Such a liquid formulation may beadministered directly per os (p.o., by mouth) or filled into a softgelatin capsule. The pharmaceutical compositions according to theinvention may be delivered in a therapeutically effective amount. Theprecise therapeutically effective amount is that amount of thecomposition that will yield the most effective results in terms ofefficacy of treatment in a given subject. This amount will varydepending upon a variety of factors, including but not limited to thecharacteristics of the therapeutic compound (including activity,pharmacokinetics, pharmacodynamics, and bioavailability), thephysiological condition of the subject (including age, sex, disease typeand stage, general physical condition, responsiveness to a given dosage,and type of medication), the nature of the pharmaceutically acceptablecarrier or carriers in the formulation, and the route of administration.One skilled in the clinical and pharmacological arts will be able todetermine a therapeutically effective amount through routineexperimentation, for instance, by monitoring a subject's response toadministration of a compound and adjusting the dosage accordingly.

Various methods may be utilized to administer the compositionscomprising steroid hormones, including but not limited to aerosol,nasal, oral, subcutaneous, transmucosal, transdermal, parenteral,implantable pump, continuous infusion, topical application, capsules,injections, intradermally, intravenously, intramuscularly,intraperitonealy, rectally, non-vaginally and/or vaginally. In oneembodiment of the claimed invention, the steroid hormone is administeredtopically or subcutaneously. In another embodiment, the steroid hormoneis administered vaginally. In another embodiment, the steroid hormone ismixed with or suspended in agents to render it soluble and is appliedtopically by placing or rubbing on the abdominal surface of pregnantpatients. Agents that render the steroid hormones soluble include butare not limited to cyclodextrins, sesame oil, fish oil, corn oil, oliveoil, coconut oil, krill oil, omega fatty acids, mineral oil, peppermintoil, flaxseed oil, vitamin E oil, argan oil, saline solution and/orglucose solution.

In one embodiment of the claimed invention, the steroid hormone is mixedwith fish oil or peppermint oil and is applied topically to prevent orinhibit preterm birth and/or delay or inhibit cervical ripening. In oneembodiment of the claimed invention, the steroid hormone is mixed withfish oil or peppermint oil and is applied topically to prevent orinhibit preterm birth and/or delay or inhibit uterine contractions. Inother embodiments, the steroid hormone is mixed with saline solution(such as isotonic saline solution) and is administered intravenously,topically, nasally or via any other route of administration so as toprevent or inhibit preterm and/or term birth by inhibiting cervicalripening and/or uterine contractility.

In some embodiments, the steroid hormone is a prosteogen. In anotherembodiment, the progestogen is 19-norprogesterone, or a pharmaceuticalequivalent, analog, derivative or a salt thereof. In another embodiment,the 19-norprogesterone pharmaceutical equivalent, derivative, analog,and/or salt thereof is trimegestone, or a pharmaceutical equivalent,analog, derivative or a salt thereof. In another embodiment, the19-norprogesterone pharmaceutical equivalent, derivative, analog, and/orsalt thereof is promegestone, nomegestrol, nomegestrol acetate,demegestone, nestorone, or a pharmaceutical equivalent, analog,derivative or a salt thereof

In various embodiments of the invention, the effective amounts of thesteroid hormone is about 0.5-1 mg/day, 1-5 mg/day, 5-10 mg/day, 10-15mg/day, 15-20 mg/day, 20-25 mg/day, 25-30 mg/day, 30-35 mg/day, 35-40mg/day, 40-45 mg/day, 45-50 mg/day, 50-55 mg/day, 55-60 mg/day, 60-65mg/day, 65-70 mg/day, 70-75 mg/day, 75-80 mg/day, 80-85 mg/day, 85-90mg/day, 90-95 mg/day or 95-100 mg/day, 100-200 mg/day, 200-300 mg/day,300-400 mg/day, 400-500 mg/day, 500-600 mg/day, 600-700 mg/day, 700-800mg/day, 800-900 mg/day, 900-1000 mg/day, 1000-1100 mg/day, 1100-1200mg/day, 1200-1300 mg/day, 1300-1400 mg/day, 1400-1500 mg/day, 1500-1600mg/day, 1600-1700 mg/day, 1700-1800 mg/day, 1800-1900 mg/day, 1900-2000mg/day, 2000-2100 mg/day, 2100-2200 mg/day, 2200-2300 mg/day, 2300-2400mg/day, 2400-2500 mg/day, 2500-2600 mg/day, 2600-2700 mg/day, 2700-2800mg/day, 2800-2900 mg/day, 2900-3000 mg/day, 3000-3100mg/day, 3100-3200mg/day, 3200- 3300 mg/day, 3300-3400 mg/day, 3400-3500 mg/day,3500-3600 mg/day, 3600-3700 mg/day, 3700-3800 mg/day, 3800-3900 mg/day,3900-4000 mg/day, 4000-4200 mg/day, 4200-4400 mg/day, 4400-4600 mg/day,4600-4800 mg/day or 4800-5000 mg/day. In some embodiments, the steroidhormone is a prosteogen. In another embodiment, the progestogen is19-norprogesterone, or a pharmaceutical equivalent, analog, derivativeor a salt thereof. In another embodiment, the 19-norprogesteronepharmaceutical equivalent, analog, derivative or a salt thereof istrimegestone, or a pharmaceutical equivalent, analog, derivative or asalt thereof. In another embodiment, the 19-norprogesteronepharmaceutical equivalent, analog, derivative or a salt thereof ispromegestone, nomegestrol, nomegestrol acetate, demegestone, nestorone,or a pharmaceutical equivalent, analog, derivative or a salt thereof. Invarious embodiments, the steroid hormone administered at theaforementioned dosage is trimegestone, promegestone, nomegestrol,nomegestrol acetate, demegestone, nestorone, or a pharmaceuticalequivalent, analog, derivative or a salt thereof. In one embodiment, thesteroid hormone administered at the aforementioned dosage istrimegestone, promegestone, nomegestrol, nomegestrol acetate,demegestone, nestorone, or a pharmaceutical equivalent, analog,derivative or a salt thereof and is administered daily, biweekly,weekly, every fortnight or monthly. In one embodiment, the steroidhormone administered at the aforementioned dosage is trimegestone,promegestone, nomegestrol, nomegestrol acetate, demegestone, nestorone,or a pharmaceutical equivalent, analog, derivative or a salt thereof andis administered daily.

As described above, in one embodiment of the invention the steroidhormone may be suspended in or mixed with agents that render the steroidhormone soluble. Such agents include but are not limited tocyclodextrins, sesame oil, fish oil, corn oil, olive oil, coconut oil,krill oil, omega fatty acids, mineral oil, peppermint oil, flaxseed oil,vitamin E oil, argan oil, saline solution and/or glucose solution. Theeffective amount of the agent may be about 0.05-0.1 ml/mg of steroidhormone, 0.1-0.2 ml/mg of steroid hormone, 0.2-0.3 ml/mg of steroidhormone, 0.3-0.4 ml/mg of steroid hormone, 0.4-0.5 ml/mg of steroidhormone, 0.5-0.6 ml/mg of steroid hormone, 0.6-0.7 ml/mg of steroidhormone, 0.7-0.8 ml/mg of steroid hormone, 0.8-0.9 ml/mg of steroidhormone, 0.9-1.0 ml/mg of steroid hormone, 1.0-5.0 ml/mg of steroidhormone, 5.0-10.0 ml/mg of steroid hormone, 10.0-15.0 ml/mg of steroidhormone, 15.0-20.0 ml/mg of steroid hormone, 20.0-25.0 ml/mg of steroidhormone or 25.0-30.0 ml/mg of steroid hormone. In a one embodiment,trimegestone is mixed with fish oil or peppermint oil or with salinesolution wherein the aforementioned amounts are the effective amounts ofthe fish oil or peppermint oil or saline solution. In some embodiments,the steroid hormone is a prosteogen. In another embodiment, theprogestogen is 19-norprogesterone, or a pharmaceutical equivalent,analog, derivative or a salt thereof. In another embodiment, the19-norprogesterone pharmaceutical equivalent, analog, derivative or asalt thereof is trimegestone, or a pharmaceutical equivalent, analog,derivative or a salt thereof. In another embodiment, the19-norprogesterone pharmaceutical equivalent, analog, derivative or asalt thereof is promegestone, nomegestrol, nomegestrol acetate,demegestone, nestorone, or a pharmaceutical equivalent, analog,derivative or a salt thereof.

In another embodiment of the invention, the steroid hormones may beadministered concurrently or sequentially with an effective amount ofnifedipine, indomethacin, magnesium sulfate, oxytocin antagonists suchas atosiban, and/or other tocolytics. In some embodiments of theinvention, the effective amounts of nifedipine, indomethacin, magnesiumsulfate, oxytocin antagonists such as atosiban, and/or other tocolyticsis about 0.5-1 mg/day, 1-5 mg/day, 5-10 mg/day, 10-15 mg/day, 15-20mg/day, 20-25 mg/day, 25-30 mg/day, 30-35 mg/day, 35-40 mg/day, 40-45mg/day, 45-50 mg/day, 50-55 mg/day, 55-60 mg/day, 60-65 mg/day, 65-70mg/day, 70-75 mg/day, 75-80 mg/day, 80-85 mg/day, 85-90 mg/day, 90-95mg/day or 95-100 mg/day, 100-200 mg/day, 200-300 mg/day, 300-400 mg/day,400-500 mg/day, 500-600 mg/day, 600-700 mg/day, 700-800 mg/day, 800-900mg/day, 900-1000 mg/day, 1000-1100 mg/day, 1100-1200 mg/day, 1200-1300mg/day, 1300-1400 mg/day, 1400-1500 mg/day, 1500-1600 mg/day, 1600-1700mg/day, 1700-1800 mg/day, 1800-1900 mg/day, 1900-2000 mg/day, 2000-2100mg/day, 2100-2200 mg/day, 2200-2300 mg/day, 2300-2400 mg/day, 2400-2500mg/day, 2500-2600 mg/day, 2600-2700 mg/day, 2700-2800 mg/day, 2800-2900mg/day, 2900-3000 mg/day, 3000-3100 mg/day, 3100-3200 mg/day, 3200-3300mg/day, 3300-3400 mg/day, 3400-3500 mg/day, 3500-3600 mg/day, 3600-3700mg/day, 3700-3800 mg/day, 3800-3900 mg/day, 3900-4000 mg/day, 4000-4200mg/day, 4200-4400 mg/day, 4400-4600 mg/day, 4600-4800 mg/day or4800-5000 mg/day. In some embodiments, the steroid hormone is aprosteogen. In another embodiment, the progestogen is19-norprogesterone, or a pharmaceutical equivalent, analog, derivativeor a salt thereof. In another embodiment, the 19-norprogesteronepharmaceutical equivalent, analog, derivative or a salt thereof istrimegestone, or a pharmaceutical equivalent, analog, derivative or asalt thereof. In another embodiment, the 19-norprogesteronepharmaceutical equivalent, analog, derivative or a salt thereof ispromegestone, nomegestrol, nomegestrol acetate, demegestone, nestorone,or a pharmaceutical equivalent, analog, derivative or a salt thereof.

Typical dosages of an effective amount of a steroid hormone, such astrimegestone, promegestone, nomegestrol, nomegestrol acetate,demegestone, nestorone, or a pharmaceutical equivalent, analog,derivative or a salt thereof, can be in the ranges recommended by themanufacturer where known therapeutic compounds are used, and also asindicated to the skilled artisan by the in vitro responses or responsesin animal models. The same or similar dosing can be used in accordancewith various embodiments of the present invention, or an alternatedosage may be used in connection with alternate embodiments of theinvention, with or without oil, nifedipine or indomethacin. The actualdosage can depend upon the judgment of the physician, the condition ofthe patient, and the effectiveness of the therapeutic method based, forexample, on the in vitro responsiveness of relevant cultured cells orhistocultured tissue sample, or the responses observed in theappropriate animal models.

The subjects treated by the present invention include mammaliansubjects, including but not limited to human, monkey, ape, dog, cat,cow, horse, goat, pig, rabbit, mouse and rat.

In one embodiment, the subject is human. In a different embodiment, thehuman subject is administered a steroid hormone beginning at about the16^(th) week up to the 37^(th) week of gestation, beginning at about18^(th) week up to about 22^(nd) week of gestation, beginning at about18^(th) week up to about 35^(th) week of gestation, beginning at about18^(th) week up to about 37^(th) week of gestation, beginning at thetime of positive pregnancy until the 37^(th) week of gestation orbeginning at the time preterm labor is suspected up to when time ofdelivery is imminent. In an embodiment, the steroid hormone is mixedwith or suspended in agents to render the steroid hormones soluble andis applied topically. In some embodiments, the steroid hormone is mixedwith fish oil, peppermint oil or with omega fatty acids and is appliedtopically, for example, by placing or rubbing the 19-norprogesterone orpharmaceutical equivalent, derivative, analog, and/or salt thereof mixedin oil on the abdominal surface of a pregnant woman. In one embodiment,the steroid hormone is mixed with saline solution (such as isotonicsaline solution) and is administered intravenously, topically, nasallyor via any other route of administration. In some embodiments, thesteroid hormone is a prosteogen. In another embodiment, the progestogenis 19-norprogesterone, or a pharmaceutical equivalent, analog,derivative or a salt thereof. In another embodiment, the19-norprogesterone pharmaceutical equivalent, analog, derivative or asalt thereof is trimegestone, or a pharmaceutical equivalent, analog,derivative or a salt thereof. In another embodiment, the19-norprogesterone pharmaceutical equivalent, analog, derivative or asalt thereof is promegestone, nomegestrol, nomegestrol acetate,demegestone, nestorone, or a pharmaceutical equivalent, analog,derivative or a salt thereof.

In another embodiment, the human subject is administered a steroidhormone for about 2 to 4 weeks, for about 4 to 6 weeks, for about 6 to 8weeks, for about 8 to 10 weeks, for about 10 to 12 weeks, for about 12to 14 weeks, for about 14 to 19 weeks, for about 20 weeks, for about 21weeks, for about 22 weeks, for about 23 weeks, for about 25 weeks, forabout 26 weeks, for about 27 weeks, for about 28 weeks or for about 29weeks, for about 30 weeks, for about 35 weeks or for about 37 weeks. Inan embodiment, the steroid hormone is mixed with or suspended in agentsto render the steroid hormones soluble and is applied topically. In oneembodiment, the steroid hormone is mixed with fish oil, peppermint oilor with omega fatty acids and is applied topically, for example, byplacing or rubbing the 19-norprogesterone or pharmaceutical equivalent,derivative, analog, and/or salt thereof mixed in oil on the abdominalsurface of a pregnant woman. In other embodiments, the steroid hormoneis mixed with saline solution (such as isotonic saline solution) and isadministered intravenously, topically, nasally or via any other route ofadministration. In another embodiment, the progestogen is19-norprogesterone, or a pharmaceutical equivalent, analog, derivativeor a salt thereof. In another embodiment, the 19-norprogesteronepharmaceutical equivalent, analog, derivative or a salt thereof istrimegestone, or a pharmaceutical equivalent, analog, derivative or asalt thereof. In another embodiment, the 19-norprogesteronepharmaceutical equivalent, analog, derivative or a salt thereof ispromegestone, nomegestrol, nomegestrol acetate, demegestone, nestorone,or a pharmaceutical equivalent, analog, derivative or a salt thereof.

In a further embodiment, the human subject is administered a steroidhormone when the pregnant woman's cervix length is greater than 1.0 cm,or when the cervix length is less than or equal to about 3.0 cm, or whenthe cervix length is between 1.0 and 8.0 cm. In an embodiment, thesteroid hormone is mixed with or suspended in agents to render thesteroid hormones soluble and is applied topically. In some embodiments,preterm birth is associated with shorter cervix length. For example,women with cervical lengths at or below the 25^(th), 50^(th) and 75^(th)percentile (i.e., less than 3.0 cm) at 24 weeks may possess increasedrisk of preterm birth, whereas women with cervical lengths above the75^(th) percentile (i.e., greater than 4.0 cm) may possess decreasedrisk of preterm birth. In some embodiments, cervical length may be usedas a basis for determining a schedule and dosage for administering asteroid hormone. In other embodiments, preterm delivery is associatedwith an increase in prostaglandin levels, such as prostaglandin E2. Insome embodiments, prostaglandin expression levels in the pregnant mothermay be used as a basis for determining a schedule and dosage foradministering a steroid hormone. In some embodiments, the steroidhormone is a proesetogen. In another embodiment, the progestogen is19-norprogesterone, or a pharmaceutical equivalent, analog, derivativeor a salt thereof. In another embodiment, the 19-norprogesteronepharmaceutical equivalent, derivative, analog, and/or salt thereof istrimegestone, or a pharmaceutical equivalent, analog, derivative or asalt thereof. In another embodiment, the 19-norprogesteronepharmaceutical equivalent, derivative, analog, and/or salt thereof ispromegestone, nomegestrol, nomegestrol acetate, demegestone, nestorone,or a pharmaceutical equivalent, analog, derivative or a salt thereof.

In some embodiments, the steroid hormone is mixed with fish oil or withomega fatty acids or with cyclodextrins and is applied topically, forexample, by placing or rubbing the 19-norprogesterone or pharmaceuticalequivalent, derivative, analog, and/or salt thereof, such astrimegestone, mixed in oil on the abdominal surface of a pregnant woman.In other embodiments, the steroid hormone is mixed with saline solution(such as isotonic saline solution) and is administered intravenously,topically, nasally or via any other route of administration. In anotherembodiment, the progestogen is 19-norprogesterone, or a pharmaceuticalequivalent, analog, derivative or a salt thereof. In another embodiment,the 19-norprogesterone pharmaceutical equivalent, analog, derivative ora salt thereof is trimegestone, or a pharmaceutical equivalent, analog,derivative or a salt thereof. In another embodiment, the19-norprogesterone pharmaceutical equivalent, analog, derivative or asalt thereof is promegestone, nomegestrol, nomegestrol acetate,demegestone, nestorone, or a pharmaceutical equivalent, analog,derivative or a salt thereof.

In various embodiments, the steroid hormones are in a soluble form,crystalline form, gel form, tablet form or encapsulated form. In someembodiments, the steroid hormone is a prosteogen. In another embodiment,the progestogen is 19-norprogesterone, or a pharmaceutical equivalent,analog, derivative or a salt thereof. In another embodiment, the19-norprogesterone pharmaceutical equivalent, analog, derivative or asalt thereof is trimegestone, or a pharmaceutical equivalent, analog,derivative or a salt thereof. In another embodiment, the19-norprogesterone pharmaceutical equivalent, analog, derivative or asalt thereof is promegestone, nomegestrol, nomegestrol acetate,demegestone, nestorone, or a pharmaceutical equivalent, analog,derivative or a salt thereof.

As described herein, the present invention further provides a kit totreat and/or inhibit preterm and/or term delivery. The kit is anassemblage of materials or components, including at least one of theinventive compositions. Thus, in some embodiments the kit contains acomposition including 19-norprogesterone or pharmaceutical equivalent,derivative, analog, and/or salt thereof, such as trimegestone, fortopical application, as described above.

In one embodiment, the kit is configured particularly for the purpose oftreating mammalian subjects. In another embodiment, the kit isconfigured particularly for the purpose of treating human subjects. Infurther embodiments, the kit is configured for veterinary applications,treating subjects such as, but not limited to, farm animals, domesticanimals, and laboratory animals.

Instructions for use may be included in the kit. “Instructions for use”typically include a tangible expression describing the technique to beemployed in using the components of the kit to effect a desired outcome,such as to apply 19-norprogesterone or pharmaceutical equivalent,derivative, analog, and/or salt thereof, such as trimegestone,topically. Optionally, the kit also contains other useful components,such as, diluents, buffers, pharmaceutically acceptable carriers,syringes, catheters, applicators, pipetting or measuring tools,bandaging materials or other useful paraphernalia as will be readilyrecognized by those of skill in the art.

The materials or components assembled in the kit can be provided to thepractitioner stored in any convenient and suitable ways that preservetheir operability and utility. For example the components can be indissolved, dehydrated, or lyophilized form; they can be provided atroom, refrigerated or frozen temperatures. The components are typicallycontained in suitable packaging material(s). As employed herein, thephrase “packaging material” refers to one or more physical structuresused to house the contents of the kit, such as inventive compositionsand the like. The packaging material is constructed by well-knownmethods, preferably to provide a sterile, contaminant-free environment.

As disclosed herein, the inventors compared and evaluate the inhibitoryeffects of trimegestone (TMG) and progesterone (P4) (micronized) andhave established TMG as a novel treatment for term and preterm laborwith significant effects on the delay of delivery.

Delay and block of delivery occurs when both P4 and TMG are administeredlate in gestation in pregnant rat and guinea pig animal models. However,TMG exhibits remarkable drug efficacy, achieving the same inhibition asP4, but at much lower doses. These effects of TMG on processes ofcervical ripening and uterine contraction provide a novel approach fortreating preterm and/or term labor, along with improved methods ofadministration. Other diseases and/or conditions may be treated withTMG, such as dysmenorrhea or luteal insufficiency for sustainingpregnancy.

EXAMPLES

The following examples are provided to better illustrate the claimedinvention and are not to be interpreted as limiting the scope of theinvention. To the extent that specific materials are mentioned, it ismerely for purposes of illustration and is not intended to limit theinvention. One skilled in the art may develop equivalent means orreactants without the exercise of inventive capacity and withoutdeparting from the scope of the invention.

Example 1 Generally

Trimegestone (TMG), a 19-norpregnane progestin, has been used inclinical trials as a proposed treatment for hormone replacement therapy.TMG binds to the human progesterone receptor with greater affinity (6times) than progesterone (P4). TMG lacks masculinization or feminizationeffects of the fetus, making it a suitable candidate for use duringpregnancy. The inventors compared and evaluated the inhibitory effectsof TMG and P4 (micronized), both given topically and parenterally onterm delivery in pregnant rats and to assess the ability of TMG tosuppress preterm delivery in pregnant guinea pigs. Additionalexperiments were performed to confirm sex ratios of delivered animalsand to establish sustained fertility.

Example 2 In Vivo Rat Study Design

Pregnant rats, a well-known model for the study of pregnancy in animals,are incredibly sensitive to changes in progesterone levels with preterm,term, or delayed delivery when progesterone levels are altered or whenprogesterone receptor agonists/antagonists are utilized.²⁸ The highsensitivity of rat models to changes in progesterone levels demonstratea decline in progesterone as producing preterm birth while highprogesterone levels at term will delay delivery. This allows one topredict with high probability, the effects of progestins, such as TMG,on both term labor and preterm labor.

Timed-pregnant Sprague-Dawley rats (200-250 g) from Charles-RiverLaboratories (Wilmington, Mass., USA) were delivered to our animal carefacilities on day 15 of gestation (day 1 being the day when a sperm plugwas observed). The animals were housed separately, with free access tofood and water and maintained on a constant 12-hour light-dark cycle.Control pregnant rats were spontaneously delivering on day 22 ofgestation. The animals were randomly allocated into groups andsacrificed by carbon dioxide inhalation on day 5 postpartum or on day 25of gestation in the groups with delayed delivery.

Pregnant rats (N=6 per group) were treated, when not otherwisementioned, from day 20 of gestation until delivery. Single dailytreatments were performed at 8 am and twice a day treatments at 8 am and8 pm. Treatment began daily on day 20 of gestation with vehicles or: a)Topical P4 at various doses (4-30 mg/day, vehicle (v)=fish oil) ortopical TMG (0.5-2 mg/day, v=fish oil; b) Subcutaneous (s.c.) P4 (0.5-4mg/day, v=sesame oil) or s.c. TMG (0.5-2 mg/day, v=benzyl benzoate(BB)and castor oil (CO), 1:4). Delivery times were observed. Time ofdelivery =hours after 8 am on day 22 of gestation, 80 hours =completeblock of delivery and time of sacrifice.

Example 3 Reagents

Micronized progesterone (used for topical and subcutaneousadministration in rats) was purchased from Spectrum Chemical MFG Corp.(Gardena, Calif., USA). PGE2 (used for inducing preterm labor in guineapigs was purchased from Tocris Bioscience (Ellisville, Mo., USA).Trimegestone purchased from Taizhou Jiakan Chemical Co. Ltd. (Zheijiang,China) and tested for purity by Evestra (San Antonio, Tex.).

Example 4 In Vivo Rat Study: Methods Of Administration

Subcutaneous treatments. All daily injections were by the subcutaneousroute (s.c) in fish oil for the P4 treatments and benzyl benzoate (BB, 1part): castor oil (CO, 4 parts) for the TMG group. P4 and TMG had doseranges of .5mg-4mg per day and .5mg-2mg per day, respectively. Vehiclesonly are used in the control groups.

Topical treatments. Topical P4 and TMG (in fish oil and benzylbenzoate:castor oil (1:4), respectively) treatments were applied to theshaved back of the rat twice a day For topical treatments of P4 and TMG,dose range from 2 mg-30 mg per day and 0.005 to 0.5mg per day,respectively.

Example 5 In Vivo Rat Study: Sexing And Fertility

To determine the effects of TMG on progeny sex ratios, pregnant rats(N=9 per group) were treated daily beginning on day 13 of gestation withTMG (in benzyl benzoate+ castor oil, vehicle) or with vehicle only.Because TMG inhibits delivery in pregnant rats, on day 22 of gestation,TMG-treated rats were sacrificed and pups were removed from the uterusand placed with surrogate rat. Pups were then placed with surrogatemother also on day 22 of gestation whose pups were sacrificed.

To determine the effects of TMG on fertility the following procedure wasfollowed. When pups from TMG-treated pregnant rats were of breeding age(5 months) the females were placed with normal (untreated) males for 6days. Similarly, male pups from TMG-treated rats were placed with normal(untreated) females for 6 days. The ability of the pups to produceoffspring was not compromised by the TMG treatments.

Example 6 In Vivo Rat Study: Determining Changes In Delivery Time

Times of delivery of controls and treatment groups were determined ashours after 8 a.m. on day 22 of gestation. An 80-hour delay isclassified as complete block of delivery (i.e. 100% inhibition). Delaysin delivery less than 80 hours were calculated as less than 100%inhibition. The expulsion of a single pup was noted as delivery. Controlgroups spontaneously delivered on day 22 of gestation.

Example 7 In Vivo Guinea Pig Study

Pregnant guinea pigs, another model of pregnancy are also utilized asthey more closely resemble the endocrine control of human pregnancy withprogesterone levels in pregnancy maintained by the placenta as opposedto the ovaries, which is observed in pregnant rats.

Pregnant Hartley guinea pigs arrived at our facilities at 31-35 daysgestation and housed in pairs, with free access to food and water andalso maintained on a constant 12-hour light-dark cycle. The animals wereeuthanized with a combination of xylazine (Gemini; Burns VeterinarySupply Inc, Rockville Center, N.Y.) and ketamine HCL (Ketaset; FortDodge Laboratories Inc, Fort Dodge, Iowa). All procedures were approvedby the Animal Care and Use Committee of the St. Joseph's Hospital andMedical Center in Phoenix, Ariz.

Pregnant guinea pigs (N=4-6 per group) were allocated into 4 groups(Vehicle (v) only, TMG only, PGE2 only, PGE2+TMG). PGE2 administration(3mg/day s.c, v =saline) began daily on day 46 to day 47 of gestation.TMG administration (4 mg/day s.c v=BB:CO) began daily on day 44 untilday 47 of gestation. All guinea pigs were sacrificed on day 48.

Example 8 Statistical Analyses

The Student's t test was used to compare the treatment groups with itsspecific control groups to determine the differences in delivery times.A 2-tailed probability value of P<0.05 was considered statisticallysignificant.

Example 9 Effects Of Treatments On Time Of Delivery In Pregnant Rats

As shown in FIGS. 1-4, the inventors discovered that TMG completelyblocks term delivery in rats (80 hrs. inhibition) at much lower doses(ca. 30×, 0.5 mg TMG vs. 15 mg P4, P<0.05, topically, and ca. 4×, 0.5 mgTMG vs. 2 mg P4, P<0.05, s.c) when compared to P4.

FIG. 5 further summarizes the results of the different treatment groupson time of delivery and shows multiple doses of subcutaneoustrimegestone (TMG) and progesterone (P4). Complete block of delivery wasobserved at 0.5 mg/day TMG and 2 mg/day P4. FIG. 6 shows the results oftime of delivery after topical treatment with TMG or P4. Complete blockof delivery was seen at 0.1 mg/day TMG and 15 mg/day P4. FIG. 7establishes a dose response for topical and subcutaneous P4. 2 mg of P4necessary for complete block of delivery, subcutaneously and 15 mg P4needed for topical treatments. FIG. 8 details topical and subcutaneoustreatments of TMG where 0.1 mg/day blocks delivery, topically, and 0.5mg/day blocks delivery subcutaneously. These results clearly show thatTMG is a highly potent and effective molecule for inhibiting term andpreterm labor, even when compared to leading compound P4.

Example 10 Effects of Treatments of TMG on Rat Pup Sex

As described, the sex of the pups was evaluated 21 days post-partum byexamining external genitalia as well as distance between rectum andgenitalia. TMG demonstrated no significant difference in the ratio ofmale to female pups when compared to control groups (FIG. 9).

Example 11 Effects of TMG Treatment on Fertility.

Similarly fertility of the offspring (both male and females) ofTMG-treated rats was not compromised by the treatment. Females (n=6)from TMG-treated rats became pregnant following breeding with normal(untreated) males and similarly males (n=6) from TMG-treated rats matedsuccessfully with normal (untreated) females to produce offspring

Example 12 Effects of Treatments of PGE2, TMG on Guinea Pig Pregnancy

TMG effectively inhibited preterm delivery stimulated by administrationof PGE2 in the pregnant guinea pig when administered mid-gestation.(FIG. 11) The inventors found that in guinea pigs, PGE2 effectivelyinduces preterm delivery, and this is inhibited by simultaneoustreatment with TMG. None of the guinea pigs treated with TMG and PGE2delivered, while ⅔ PGE2-only treated animals delivered (all 3 exhibitedvaginal bleeding).

Example 13 TMG Effectively Inhibits Term and Preterm Labor

As disclosed herein, it was found that TMG effectively inhibits bothterm delivery in rats and PGE2-induced preterm delivery in guinea pigs.Both topical and parenteral administration of P4 and TMG are equallyefficacious, but TMG is more potent than P4 in delaying delivery inrats. Topical TMG is be a successful and satisfactory treatment optionfor preterm and/or term labor.

This study shows that TMG can be useful in the delay of delivery atpreterm and at term. TMG has never been described for the prevention andtreatment of preterm labor and these results indicate a tremendousutility for use in the clinical setting. Both P4 and TMG were shown towork topically and subcutaneously, but TMG required much lower doseswhen compared to P4. In the rat studies, TMG proved to be effective atdelaying delivery even when administered late in gestation (day 20).This effect of TMG is consistent with other results that show P4inhibition of birth even after the cervix is already soft, therebyemphasizing a specific action of TMG on uterine contractility to preventbirth. The guinea pig studies utilizing PGE2 to stimulate preterm birthdemonstrated the lower delivery rates of animals treated with both TMGand PGE2 versus PGE2 alone. As a model of preterm birth, PGE2 inductionstudies in the pregnant guinea pig provides results consistent withanother specific action directed at inhibiting the process of cervicalripening. Thus, TMG exhibits properties of a highly efficaciousinhibitor of preterm and term labor, possessing specific actionsdirected at key steps involving both cervical ripening and uterinecontraction.

Dose response curves for the complete block of delivery in pregnant ratswere established in this study for both P4 and TMG when administeredeither topically or subcutaneously. FIGS. 5 and 6 show that much lowerdoses of TMG are required to block delivery when given either topicallyor subcutaneously most likely due to its ability to bind moreeffectively to the progesterone receptor than P4. Moreover, TMG alsodemonstrated no masculinizing or feminizing effects on the fetuses oftreated animals (FIG. 10) or on subsequent fertility of both female andmale offspring of TMG-treated rats. These results show improved methodsof administration, along with minimized risk of undesirable sideeffects.

Both topical and subcutaneous administration of P4 and TMG demonstratedprolonged delay of delivery with subcutaneous treatment groups requiringless dosage except in the topical vs. subcutaneous TMG treatmentexperiment. Topical TMG worked more effectively at delaying deliverythan subcutaneous administration. This result may be explained by TMG'shalf-life of 17 hours and the twice daily administration of topical TMGversus the once daily administration of subcutaneous TMG. Without beingbound by any particular theory, the levels of TMG in the topical groupmay have remained higher throughout the course of the treatments.

These results present TMG as a novel treatment for preterm and termlabor with the TMG exhibits remarkable drug efficacy, the effects of TMGon processes of cervical ripening and uterine contraction provide anovel approach for extending pregnancy term, including reducing alikelihood of preterm and/or term labor, along with improved methods ofadministration.

The various methods and techniques described above provide a number ofways to carry out the invention. Of course, it is to be understood thatnot necessarily all objectives or advantages described may be achievedin accordance with any particular embodiment described herein. Thus, forexample, those skilled in the art will recognize that the methods can beperformed in a manner that achieves or optimizes one advantage or groupof advantages as taught herein without necessarily achieving otherobjectives or advantages as may be taught or suggested herein. A varietyof advantageous and disadvantageous alternatives are mentioned herein.It is to be understood that some preferred embodiments specificallyinclude one, another, or several advantageous features, while othersspecifically exclude one, another, or several disadvantageous features,while still others specifically mitigate a present disadvantageousfeature by inclusion of one, another, or several advantageous features.

Furthermore, the skilled artisan will recognize the applicability ofvarious features from different embodiments. Similarly, the variouselements, features and steps discussed above, as well as other knownequivalents for each such element, feature or step, can be mixed andmatched by one of ordinary skill in this art to perform methods inaccordance with principles described herein. Among the various elements,features, and steps some will be specifically included and othersspecifically excluded in diverse embodiments.

Although the invention has been disclosed in the context of certainembodiments and examples, it will be understood by those skilled in theart that the embodiments of the invention extend beyond the specificallydisclosed embodiments to other alternative embodiments and/or uses andmodifications and equivalents thereof.

Many variations and alternative elements have been disclosed inembodiments of the present invention. Still further variations andalternate elements will be apparent to one of skill in the art. Amongthese variations, without limitation, are sources and composition ofprogestogens, including 19-norprogesterone derivatives such astrimegestone, further including pharmaceutical compositions, preparationmethods, dosages, administration methods, and/or other diseases andconditions and the particular use of the products created through theteachings of the invention. Various embodiments of the invention canspecifically include or exclude any of these variations or elements.

In some embodiments, the numbers expressing quantities of ingredients,properties such as concentration, reaction conditions, and so forth,used to describe and claim certain embodiments of the invention are tobe understood as being modified in some instances by the term “about.”Accordingly, in some embodiments, the numerical parameters set forth inthe written description and attached claims are approximations that canvary depending upon the desired properties sought to be obtained by aparticular embodiment. In some embodiments, the numerical parametersshould be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and parameters setting forth the broad scopeof some embodiments of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspracticable. The numerical values presented in some embodiments of theinvention may contain certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

In some embodiments, the terms “a” and “an” and “the” and similarreferences used in the context of describing a particular embodiment ofthe invention (especially in the context of certain of the followingclaims) can be construed to cover both the singular and the plural. Therecitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided with respectto certain embodiments herein is intended merely to better illuminatethe invention and does not pose a limitation on the scope of theinvention otherwise claimed. No language in the specification should beconstrued as indicating any non-claimed element essential to thepractice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember can be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. One ormore members of a group can be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is herein deemed to contain the groupas modified thus fulfilling the written description of all Markushgroups used in the appended claims.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations on those preferred embodiments will become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Itis contemplated that skilled artisans can employ such variations asappropriate, and the invention can be practiced otherwise thanspecifically described herein. Accordingly, many embodiments of thisinvention include all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above citedreferences and printed publications are herein individually incorporatedby reference in their entirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that can be employed can be within thescope of the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention can be utilized inaccordance with the teachings herein. Accordingly, embodiments of thepresent invention are not limited to that precisely as shown anddescribed.

REFERENCES

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1. A method of extending pregnancy term in a subject in need thereof,comprising: providing a quantity of a composition comprising a19-norprogesterone, or a pharmaceutical equivalent, derivative, analog,and/or salt thereof; and administering the quantity of the compositionto the subject in need thereof.
 2. The method of claim 1, wherein the19-norprogesterone comprises a compound of the formula:

(Formula 1), or a pharmaceutical equivalent, derivative, analog, and/orsalt thereof.
 3. The method of claim 1, wherein the composition furthercomprises one or more solubilizing factors.
 4. The method of claim 3,wherein the one or more solubilizing factors is selected from the groupconsisting of: cyclodextrins, sesame oil, fish oil, corn oil, olive oil,coconut oil, krill oil, omega fatty acids, mineral oil, peppermint oil,flaxseed oil, vitamin E oil, argan oil, saline solution and glucosesolution.
 5. The method of claim 1, wherein the composition isadministered through nasal, oral, subcutaneous, transmucosal,transdermal, parenteral, implantable pump, continuous infusion, topical,intradermal, intravenous, intramuscular, intraperitoneal, inhalation,rectal, non-vaginal and/or vaginal delivery.
 6. The method of claim 1,further comprising administering of one or more compounds selected fromthe group consisting of: nifedipine, indomethacin, magnesium sulfate,oxytocin antagonists, and tocolytics.
 7. The method of claim 6, whereinthe one or more compounds is administered after administering thequantity of the composition comprising a 19-norprogesterone, or apharmaceutical equivalent, derivative, analog, and/or salt thereof. 8.The method of claim 1, wherein the composition is administered at leasttwice daily.
 9. The method of claim 1, wherein the composition isadministered to the subject in the range of: 0.01-0.1 mg, 0.1-0.5 mg0.5-1 mg, 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, and/or 20-100 mg.
 10. Themethod of claim 1, wherein the pregnancy term is at least 22 weeks. 11.The method of claim 1, wherein the pregnancy term is at least 37 weeks.12. A pharmaceutical composition, comprising a therapeutically effectiveamount of a 19-norprogesterone, or a pharmaceutical equivalent,derivative, analog, and/or salt thereof, and a pharmaceuticallyacceptable carrier.
 13. The pharmaceutical composition of claim 12,wherein the 19-norprogesterone comprises a compound of the formula:

(Formula 1), or a pharmaceutical equivalent, derivative, analog, and/orsalt thereof.
 14. The pharmaceutical composition of claim 12, whereinthe composition further comprises one or more solubilizing factors. 15.The pharmaceutical composition of claim 14, wherein the one or moresolubilizing factors is selected from the group consisting of:cyclodextrins, sesame oil, fish oil, corn oil, olive oil, coconut oil,krill oil, omega fatty acids, mineral oil, peppermint oil, flaxseed oil,vitamin E oil, argan oil, saline solution and glucose solution.
 16. Thepharmaceutical composition of claim 12, further comprising one or morecompounds selected from the group consisting of: nifedipine,indomethacin, magnesium sulfate, oxytocin antagonists, and tocolytics.17. The pharmaceutical composition of claim 12 provided in a dosage inthe range of: 0.01-0.1 mg, 0.1-0.5 mg 0.5-1 mg, 1-5 mg, 5-10 mg, 10-15mg, 15-20 mg, and/or 20-100 mg.
 18. A method of treating a diseaseand/or condition in a subject in need thereof, comprising: providing aquantity of a composition comprising a 19-norprogesterone, or apharmaceutical equivalent, derivative, analog, and/or salt thereof; andadministering the quantity of the composition to the subject in needthereof.
 19. The method of claim 18, wherein the 19-norprogesteronecomprises a compound of the formula:

(Formula 1), or a pharmaceutical equivalent, derivative, analog, and/orsalt thereof.
 20. The method of claim 18, wherein the compositionfurther comprises one or more solubilizing factors.
 21. The method ofclaim 20, wherein the one or more solubilizing factors is selected fromthe group consisting of: cyclodextrins, sesame oil, fish oil, corn oil,olive oil, coconut oil, krill oil, omega fatty acids, mineral oil,peppermint oil, flaxseed oil, vitamin E oil, argan oil, saline solutionand glucose solution.
 22. The method of claim 18, wherein thecomposition is administered through nasal, oral, subcutaneous,transmucosal, transdermal, parenteral, implantable pump, continuousinfusion, topical, intradermal, intravenous, intramuscular,intraperitoneal, inhalation, rectal, non-vaginal and/or vaginaldelivery.
 23. The method of claim 18, wherein composition furthercomprises administering one or more compounds selected from the groupconsisting of: nifedipine, indomethacin, magnesium sulfate, oxytocinantagonists, and tocolytics.
 24. The method of claim 23, wherein the oneor more compounds is administered after administering the quantity ofthe composition comprising a 19-norprogesterone, or a pharmaceuticalequivalent, derivative, analog, and/or salt thereof.
 25. The method ofclaim 18, wherein the composition is administered twice daily.
 26. Themethod of claim 18, wherein the composition is administered to thesubject in the range of: 0.01-0.1 mg, 0.1-0.5 mg 0.5-1 mg, 1-5 mg, 5-10mg, 10-15 mg, 15-20 mg, and/or 20-100 mg.
 27. The method of claim 18,wherein the disease and/or condition is selected from the groupconsisting of: preterm labor, term labor, luteal insufficiency,dysmenorrhea, dysfunctional uterine bleeding, and combinations thereof.28. The method of claim 27, wherein the disease and/or condition isdysmenorrhea.
 29. The method of claim 27, wherein the disease and/orcondition is luteal insufficiency.